Effect of TGF-α on response to lapatinib and capecitabine among patients with trastuzumab-resistant HER2-positive breast cancer

Abstract

Background: In breast cancer with overexpression of human epidermal growth factor receptor 2 (HER2), targeted therapy such as trastuzumab or lapatinib is the standard of care and improved prognosis. Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and HER2. Lapatinib and capecitabine combination therapy is effective in trastuzumab-resistant HER2-positive breast cancer. However, a significant proportion of women with HER2-positive breast cancer does not respond or eventually develop resistance to lapatinib and capecitabine therapy. Hence identifying biomarker to predict response is important to personalized therapy. The previous studies investigating the correlation between extracellular domains (ECD) and downstream molecules of EGFR family and tumor response did not clearly identify any biomarker predicted for differential benefit for lapatinib yet. In this study, we investigated the biomarkers including ECD of EGFR and HER2, and major ligands of EGFR from blood of patients receiving lapatinib and capecitabine in trastuzumab-resistant HER2-positive breast cancer.

Methods: Patients received lapatinib 1250 mg once daily and capecitabine 2000 mg/m2/day, day 1 to 14, every 3 weeks. Blood samples were obtained prior to treatment initiation. Levels of transforming growth factor-α (TGF-α), epidermal growth factor (EGF), ECD of EGFR and HER2 were measured by enzyme-linked immunosorbent assay. The effect of TGF-α on in vitro sensitivity of SK-BR-3 cells to lapatinib was investigated.

Results: Among 126 patients enrolled in the Lapatinib Expanded Access Program, 64 patients who agreed to participate in the pharmacogenomic study were included in this study. Response rate was significantly higher in patients with low TGF-α (≤ 3.75 pg/ml) compared to high TGF-α (> 3.75 pg/ml) [61.1% (11/18) vs. 17.4 % (8/46), respectively; p = 0.001]. Low TGF-α was independently associated with better response in multivariate analysis [adjusted odds ratio, 8.96; 95% confidence interval (CI), 2.4 - 34.2]. Time-to-progression tended to be shorter in patients with high TGF-α compared to low TGF-α [median 3.8 months (95% CI, 2.3-5.4) vs. 6.5 (95% CI, 6.1-6.8), respectively; p = 0.067]. We confirmed that TGF-α diminished the sensitivity of SK-BR3-cells to lapatinib in vitro. The in vitro antiproliferative effect of cetuximab in combination with lapatinib was higher than that of lapatinib alone in SK-BR3-cells exposed to TGF-α.

Conclusion: These data suggest that TGF-α plays a role in resistance to lapatinib and capecitabine therapy among HER2-overexpressed breast cancer. And our result shows that anti-EGFR antibody, such as cetuximab, combined with lapatinib-based regimen is a reasonable approach to increase sensitivity to lapatinib for HER2-positive breast cancer patients with high TGF-α in blood.